PROJECT SUMMARY/ ABSTRACT Prostate cancer remains a worldwide public health issue and cause of mortality, with annual diagnosis and mortality rates exceeding 1.1 billion and 307 million patients, respectively.1 Brachytherapy is widely accepted and utilized in the management of prostate cancer. Due to recent evidence showing improved disease control in patients with potentially lethal cancers using approaches incorporating brachytherapy, its utilization is expected to increase. Successful brachytherapy hinges on adequately dosing prostate while avoiding excessive radiation to adjacent tissues. Well-recognized contributors to poor dosimetry are source positioning errors, poor source visualization and edema, which in aggregate lead to regions of excessive as well as inadequate dose. In response to the recognized need for dynamic visualization of sources and intraoperative dose analysis during the procedure, our work has led to the development of a system of intraoperative ultrasound and fluoroscopy (iRUF) dynamic dose calculation using fluoroscopy-based seed reconstruction and fusion with intraprocedure ultrasound imaging. Following our pilot feasibility trial, we developed an FDA-approved dedicated brachytherapy platform, and have confirmed this technique in a Phase II trial, with outstanding dosimetry on a consistent basis.2,3 Currently, whole-gland treatment is standard in prostate cancer therapy. The need for whole-gland treatment stems from the uncertainty and difficulty in precisely identifying tumor foci within. Unfortunately, such approaches inevitably result in radiation exposure of adjacent critical structures, with potential toxicity and permanent quality of life effects. As long as whole gland therapy is delivered, the ability to limit normal tissue doses remains constrained by their proximity. New advances in PET imaging targeting Prostate Specific Membrane Antigen (PSMA) and second-generation PSMA-binding agents now allow highly specific and sensitive identification of extraprostatic and intraprostatic tumors.4,5,6 Focal therapy using PSMA PET/CT-and dynamic dosimetry-guided seed placement promises to further improve the standard of care in brachytherapy, allowing the physician to precisely tailor the dose to the individual?s tumor. This requires precise tumor imaging combined with dynamic intra-operative localization of the implant in relation to the target volume, as well as surrounding uninvolved prostate and normal anatomy.7,8,9,10 Combining iRUF and PSMA PET/CT would break new ground through addition of precise targeting via purely computational methods. We aim to develop a clinically feasible image-guidance platform for dynamic, quantitative evaluation of partial-gland, focal dosimetry during brachytherapy. The system would allow personalized brachytherapy, achieving excellent cancer control while avoiding unnecessary toxicity for prostate cancer survivors.